Annually 785,000 people in the United States suffer from myocardial infarction (MI). MI often results in decreased contractility, electrical instabilit, and tissue necrosis in the heart leading to lethal cardiac arrhythmias and 22% of men and 46% of women are diagnosed with heart failure (HF) within six years. Stem cell therapy has gained relevance as a technique to repair the damaged myocardium. However, while this treatment shows great promise, there are limitations. One such limitation is after transplantation, only a very low percentage of the injected cells remain in the injured myocardium, known as low cell engraftment rate. This critical issue needs to be addressed before stem cell therapies can be applied in clinical settings. This research aims at addressing this limitation and improving cardiac stem cell therapies for the treatment of MI and MI-induced HF. Vagal nerve stimulation (VNS) is a contemporaneous emerging potential therapy for the treatment of injured hearts. VNS has been shown to 1) greatly reduce inflammation and 2) markedly suppress arrhythmias in animals with MI. Our major hypothesis is that the anti-inflammatory mechanism of VNS will result in an increase in stem cell engraftment while the anti-arrhythmic effects of VNS will reduce the likelihood of arrhythmias associated with MI injury and/or stem cell transplantation. We propose to implement three specific aims in order to test our hypothesis. First, we aim to determine the optimal time for the onset of VNS to obtain maximal anti- inflammatory effects. Specifically, we will investigate four different timings of VNS, i.e. 1) 30 minutes prior to ischema, 2) at the onset of ischemia, 3) 15 minutes at ischemia, or 4) at the onset of reperfusion, and precisely determine which will provide the optimal benefits. After determining this optimal time, we will use this time to complete our remaining two aims. Second, we aim to study the long term anti-inflammatory effects of VNS and stem cell engraftment rate to test our hypothesis that VNS therapy is able to create an intramyocardial microenvironment more receptive to stem cell transplantation and differentiation due to its anti-inflammatory effects, and thus, increase engraftment rate. Third, we aim to perform telemetric ECG and blood pressure measurements, echocardiography, in vivo ventricular fibrillation induction, and optical mapping experiments to assess the electrophysiological and functional effects of the combined VNS and stem cell therapy to test our hypothesis that stem cell transplantation in combination with active VNS will result in higher levels of stem cell engraftment, and thus, an enhanced healing of the damaged heart. We anticipate that the outcome of this work will be pivotal in the development of a novel combination therapy to treat MI patients.